Unlocking the power of mRNA vaccines and therapies

By Pratik Avhad, senior analyst, and Maria João Cruz, Ph.D., assistant research manager, UK Centre for Health Solutions

Since the start of the COVID-19 pandemic, more than 218 million cases—and more than 4.5 million COVID-related deaths—have been reported worldwide.¹ As long as the SARS-CoV-2 virus is in circulation, it will have an opportunity to mutate into potentially more infectious strains and remain an ever-moving target. Vaccines are an essential tool in the arsenal to combat this pandemic.² To date, six vaccines have been approved for emergency or full use by at least one WHO-recognized stringent regulatory authority. All of these vaccines have been proven to be safe and effective at preventing severe disease, hospitalization, and COVID-related death.³ Vaccine developers are using a variety of technologies and techniques—from the tried and tested to completely novel approaches. The first vaccine to receive emergency approval was a first-in-class synthetic messenger RNA (mRNA) vaccine⁴, making RNA a household term. Even though mRNA technology itself is not new, its clinical reality is still nascent, and this blog explores its concept and considers what future uses might emerge.

What is RNA? Its role from DNA to protein

Let’s go back to the basics of molecular biology. DNA and RNA are the two naturally occurring varieties of nucleic acids, which are the main information-carrying molecules in our cells. DNA is a long, double-stranded molecule that stores the genetic instructions your body’s cells need to make proteins. These instructions are translated from nucleic acid into protein through an intermediate messenger, mRNA. The mRNA carries that protein-encoding DNA information from the nucleus to the cytoplasm and activates the cell machinery to make fully functional proteins.⁵

mRNA as a medicine—a long-awaited therapeutic

Nucleic acids first emerged as promising therapeutics in 1990 after the publication of a report that demonstrated the successful use of mRNA and DNA injected into mice for protein production.⁶ In 1992, another study demonstrated that administration of vasopressin-encoding mRNA in the hypothalamus could elicit a physiological response in rats.⁷ Both discoveries demonstrated that synthetic mRNA molecules can be used to deliver genetic information to the translational machinery to generate the encoded proteins. RNA technology can potentially be used for the following therapeutic applications:

Replacement therapy: mRNA is administered to the patient to compensate for a defective gene/protein, or to supply therapeutic proteins
Vaccines: mRNA encoding specific antigen(s) are administered to elicit protective immunity
Cell therapy: mRNA is transfected into the cells ex vivo to alter cell phenotype or function, and these modified cells are subsequently delivered into the patient.⁸

Despite their promise, mRNA-based therapies and vaccines have faced several challenges when attempting to translate the success achieved in preclinical studies into the clinic. This has largely been due to concerns around mRNA instability and inefficient in vivo delivery. Indeed, the successful use of mRNA-based therapeutics and vaccines lies in effective in vivo delivery, as exogenous mRNA must penetrate the barrier of the lipid cell membrane to reach the cytoplasm to be translated to a functional protein.⁹ If it is not delivered intracellularly, naked mRNA is rapidly degraded in the extracellular environment. Extensive research has been focused on optimizing delivery strategies, with carrier molecules, such as lipid nanoparticles (LNPs), becoming the most prevalent delivery method for mRNA administration, and the selected method for the approved COVID-19 vaccines.^{10, 11}

These major technological innovations and research efforts deployed around the world have bolstered RNA into a promising new class of therapies with the potential to address high unmet medical needs. The use of an mRNA-based therapy shows a number of advantages over traditional small molecules or biologics (including vaccines), such as:

The ability to act on targets that are otherwise undruggable
The capability to rapidly alter the sequence of the mRNA construct for personalized treatments or to adapt to an evolving pathogen
Potential for rapid, cost-effective and scalable manufacturing (due to high yields of in vitro transcription).^{12, 13}

At present, most mRNA-based therapeutics are being used as vaccines against infectious diseases or to develop personalized cancer vaccines.¹⁴ Ongoing research is also exploring whether this technology can be used as a protein-replacement therapy, particularly for rare diseases such as the blood-clotting disorder hemophilia.¹⁵ By February 2021, there were more than 520 clinical trials testing mRNA therapeutics across more than 20 disease categories with investment growing considerably.¹⁶ Even before the pandemic, the potential of mRNA-based vaccines and therapeutics was acknowledged with market research suggesting the market value would double to US$ 6 billion by 2025 from around US$ 3 billion in 2019.¹⁷ Today, the global market value of COVID-19 mRNA vaccines has grown exponentially, and is now estimated to be worth US$ 64.9 billion, projected to grow to US$ 127.3 billion by 2027.¹⁸

mRNA and the future of vaccines in targeting infectious diseases

The success of the mRNA technology and the rapid development of safe and effective COVID-19 vaccines have exceeded most expectations. Evidence to date of its use in practice shows that mRNA vaccines have been highly effective in preventing serious disease and COVID-deaths.¹⁹ Since the onset of the pandemic, a sustained global effort to name and track SARS-CoV-2 genetic lineages has identified four viral variants of concern and seven of interest.^{20, 21} Importantly, synthetic mRNA can be easily tweaked to adapt vaccines to new, more dangerous mutations, and can be manufactured more quickly and at scale compared to traditional approaches.²²

Immense opportunities lie in leveraging this ‘platform technology’ to produce vaccines against other infectious disease-causing pathogens for which a vaccine is not yet available; and is also likely to be critical in fighting future epidemics and pandemics. Even though this technology is still new in the clinic, its immense disruptive potential as a treatment is clear and needs to be harnessed fully.

1. https://www.worldometers.info/coronavirus/

2. https://www.who.int/news-room/feature-stories/detail/getting-the-covid-19-vaccine

3. https://www.who.int/news-room/feature-stories/detail/vaccine-efficacy-effectiveness-and-protection

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938284/

5. https://www.umassmed.edu/rti/biology/what-is-rna/

6. https://www.science.org/doi/abs/10.1126/science.1690918

7. https://www.science.org/lookup/doi/10.1126/science.1546298

8. https://www.frontiersin.org/articles/10.3389/fbioe.2021.628137/full

9. https://www.nature.com/articles/nrd.2017.243

10 . https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00026-2/fulltext

11 . https://www.ft.com/content/b5d03854-39bb-48cd-9a01-5fb2a0dfbba8

12 . https://www.nature.com/articles/nrd.2017.243